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Research ArticleNEUROPHARMACOLOGY

Metabotropic Neurosteroid/ς-Receptor Involved in Stimulation of Nociceptor Endings of Mice

Hiroshi Ueda, Makoto Inoue, Akira Yoshida, Kiyonobu Mizuno, Hideko Yamamoto, Junko Maruo, Kiyoshi Matsuno and Shiro Mita
Journal of Pharmacology and Experimental Therapeutics August 2001, 298 (2) 703-710;
Hiroshi Ueda
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Makoto Inoue
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Akira Yoshida
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Kiyonobu Mizuno
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Hideko Yamamoto
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Junko Maruo
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Kiyoshi Matsuno
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Shiro Mita
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Abstract

In peripheral nociceptive flexor test, SA4503, (+)-pentazocine, and (+)-3-(hydroxyphenyl)-N-(1-propyl)piperidine, representative ς-receptor agonists, elicited dose-dependent flexor responses. These responses were blocked by ς-receptor antagonists NE-100 or BD1063, but not by pretreatments with antisense oligodeoxynucleotide for ς1 binding protein. The ς-agonists' nociception is attributed to the substance P (SP) release from nociceptor endings through activations of Gαi1 and phospholipase C (PLC). On the other hand, attomolar doses of neurosteroids such as dehydroepiandrosterone sulfate (DHEAS) and pregnenolone sulfate caused similar nociception, and they were blocked by progesterone (PROG). However, DHEAS nociception was not affected by pertussis toxin, but was completely inhibited by a PLC inhibitor or thapsigargin. Although the nociception by lower doses of DHEAS was abolished by diphenhydramine (DPH), H1 antagonist, there were dose-dependent responses by high doses of DHEAS in the presence of DPH. The responses by DHEAS in the presence of DPH were blocked by NE-100, and those by (+)-pentazocine were blocked by PROG. All these findings suggest that two novel types of neurosteroid receptors exist, neuronal NS1/ς-type, which mediates activation of Gαi1 by neurosteroids and ς-agonists, followed by SP release from nociceptor endings; and NS2 type, which mediates histamine release from mast cells by very low doses of neurosteroids.

Footnotes

  • This work was performed through a research grant from Environmental Agency, Government of Japan, and special coordination funds of the Science and Technology Agency of the Japanese government.

  • Abbreviations:
    NMDA
    N-methyl-d-aspartate
    PTX
    pertussis toxin
    SBP
    ς-binding protein
    i.pl.
    intraplantar
    DHEAS
    dehydroepiandrosterone sulfate
    PREGS
    pregnenolone sulfate
    PROG
    progesterone
    DPH
    diphenhydramine
    AS-ODN
    antisense oligodeoxynucleotide
    MS-ODN
    missense oligodeoxynucleotide
    i.t.
    intrathecal
    DRG
    dorsal root ganglion
    PAGE
    polyacrylamide gel electrophoresis
    PLC
    phospholipase C
    SP
    substance P
    InsP3
    inositol trisphosphate
    • Received December 29, 2000.
    • Accepted April 18, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 298 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 298, Issue 2
1 Aug 2001
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Research ArticleNEUROPHARMACOLOGY

Metabotropic Neurosteroid/ς-Receptor Involved in Stimulation of Nociceptor Endings of Mice

Hiroshi Ueda, Makoto Inoue, Akira Yoshida, Kiyonobu Mizuno, Hideko Yamamoto, Junko Maruo, Kiyoshi Matsuno and Shiro Mita
Journal of Pharmacology and Experimental Therapeutics August 1, 2001, 298 (2) 703-710;

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Research ArticleNEUROPHARMACOLOGY

Metabotropic Neurosteroid/ς-Receptor Involved in Stimulation of Nociceptor Endings of Mice

Hiroshi Ueda, Makoto Inoue, Akira Yoshida, Kiyonobu Mizuno, Hideko Yamamoto, Junko Maruo, Kiyoshi Matsuno and Shiro Mita
Journal of Pharmacology and Experimental Therapeutics August 1, 2001, 298 (2) 703-710;
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